Effects of Sodium/Glucose co-transporter inhibitors on contractility and Ca2+ signaling in Ventricular Myocytes from Streptozotocin-Induced diabetic rats
Abstract
The prevalence of diabetes mellitus is increasing at an alarming rate worldwide. Cardiovascular (CV) disease is the major cause of morbidity and mortality in diabetic patients. The search for new treatments has led to developing alternative insulin-independent treatment strategies such as sodium/glucose co-transporter (SGLT) inhibitors. Inhibition of intestinal SGLT1 impairs dietary glucose absorption, while inhibition of renal SGLT2 promotes glucose excretion leading to calorie loss and improved glycemic control. In this study, we hypothesized that inhibiting cardiac SGLTs may alter Ca2+ mobilization in myocytes. The effects of Phlorizin (PHLOR) (non-selective SGLT1 and 2 inhibitor), Quercetin-3-O-glucoside (QUER-3-G) (selective SGLT1 inhibitor), Dapagliflozin (DAPA) (selective SGLT2 inhibitor) on ventricular myocyte shortening and intracellular Ca2+ have been investigated in streptozotocin (STZ)-induced diabetic rats and age-matched Controls. Experiments were performed at 35-36°C after 2 months of STZ treatment. Myocyte shortening, intracellular Ca2+ and L-type Ca2+ current were measured by video edge detection in electrically-stimulated (1Hz) myocytes, by fluorescence photometry in Fura-2 loaded myocytes and by whole-cell patch clamp, respectively before and after a 5 minute application of the SGLT inhibitor (10-6 M) tested. The amplitude (AMP) of shortening was significantly (P